© 2000 American Heart Association, Inc.
Integrative Physiology |
Reduced Neointima Hyperplasia of Vein Bypass Grafts in Intercellular Adhesion Molecule-1–Deficient Mice
Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-333–I-334).
From the Institute for Biomedical Aging Research (Y.Z., M.M., Q.X.), Austrian Academy of Sciences Innsbruck, Austria; and Institute for General and Experimental Pathology (Y.H., H.D., G.W.), University of Innsbruck Medical School, Innsbruck, Austria.
Correspondence to Dr Qingbo Xu, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. E-mail Qingbo.Xu{at}oeaw.ac.at
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Abstract |
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Abstract—Recently, we established a new mouse model of vein graft arteriosclerosis through the grafting of vena cava to carotid arteries. In many respects, the morphological features of this murine vascular graft model resemble those of human venous bypass graft disease. With this model, we studied the role of intercellular adhesion molecule-1 (ICAM-1) in the development of vein graft arteriosclerosis in ICAM-1–deficient mice. Neointimal hyperplasia of vein grafts in ICAM-1 -/- mice was reduced 30% to 50% compared with that of wild-type control animals. Immmunofluorescent analysis revealed that increased ICAM-1 expression was observed on the endothelium and smooth muscle cells (SMCs) of the grafted veins in wild-type, but not ICAM-1 -/-, mice. MAC-1 (CD11b/18)–positive cells that adhered to the surface of vein grafts in ICAM-1 -/- mice were significantly less as identified with en face immunofluorescence, and these positive cells were more abundant in the intimal lesions of vein grafts in wild-type mice. Furthermore, aortic SMCs cultivated from wild-type mice exhibited high ICAM-1 expression in response to tumor necrosis factor-
. When tumor
necrosis factor-–stimulated SMCs were incubated with mouse spleen
leukocytes, the number of cells that adhered to ICAM-1 -/- SMCs was
significantly lower than the number that adhered to ICAM-1 +/+ SMCs,
which was markedly blocked through pretreatment of leukocytes with the
anti–MAC-1 antibody. Taken together, our findings demonstrate that
ICAM-1 is critical in the development of venous bypass graft
arteriosclerosis, which provides essential
information for therapeutic intervention for vein graft disease in
patients undergoing bypass surgery.
Key Words: veins • neointima • adhesion molecules • mice • arteriosclerosis
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Since Garrett and colleagues1 performed the first aortocoronary saphenous vein graft implantation in a human in May 1967, many patients have received such surgery for vascular reconstruction. Although the treatment is highly successful in the relief of symptoms and prolongs survival in patients with severe coronary artery disease, nearly all veins implanted into the arterial circulation develop intimal hyperplasia within 4 to 6 weeks, which may reduce the lumen by as much as 25%. This process in itself rarely produces significant stenosis, but it represents the foundation for the later development of venous bypass graft atheroma.2 The pathogenesis of this disease remains poorly understood, and no successful clinical treatments are available.
The neointimal lesion has an inflammatory nature characterized by mononuclear cell infiltration in the early stage of vein bypass grafts, followed by smooth muscle cell (SMC) proliferation.3 4 Activated monocytes and macrophages, which produce mitogenic, fibrogenic, and angiogenic factors that can influence tissue remodeling, are central to inflammation5 6 and may play a crucial role in the development of neointimal hyperplasia in the grafted veins. The molecular mechanism by which monocytes/macrophages are continuously recruited to the neointima of vein bypass grafts is currently unknown.
Intercellular adhesion molecule-1 (ICAM-1), a surface
glycoprotein of the immunoglobulin superfamily, contains 5
immunoglobulin-like motifs in its extracellular domain, followed by a
single transmembrane region and a short cytoplasmic
tail.7 8 The major known functions of ICAM-1 relate to its
role in cell adhesion and migration. ICAM-1 is a counterreceptor for
the ß2 leukocyte integrins MAC-1
(Mß2, CD11b/CD18) and
lymphocyte function-associated antigen-1 (LFA-1)
(Lß2, CD11a/CD18), and
their engagement results in leukocyte adhesion and transmigration
through endothelium.9 Several lines of
evidence have suggested that ICAM-1/MAC-1–dependent cellular
interaction is involved in a number of inflammatory processes and in
arteriosclerosis via mononuclear cell adhesion and
migration.10 11 12 13 However, it remains unknown whether
ICAM-1 plays a causal role in the development of vein bypass graft
arteriosclerosis.
In our previous study, we established and characterized a new model for the study of neointima formation of venous bypass grafts in mice and demonstrated the presence of abundant MAC-1+ monocytes/macrophages in the early stages of lesions in vein grafts.14 In the present study, we evaluated the role of ICAM-1 in the development of vein graft lesions with the use of ICAM-1–deficient mice and demonstrated that the local adherence of circulating monocytes to the endothelium of grafted veins is one of the earliest cellular events. Herein, we provide the first evidence that ICAM-1 plays an important role in the pathogenesis of venous bypass graft arteriosclerosis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice and Vein Graft Procedure
ICAM-1–deficient mice of the C57BL/6J strain15 were purchased from Jackson Laboratories. Three genotypes of ICAM-1 (-/-, +/-, and +/+) mice were identified.
The vein grafts were performed with animals of the same genotype as donors and recipients. The procedure used for vein grafts was similar to that described previously.14 Briefly, the vena cava vein was harvested, and the right common carotid artery was mobilized, with a cuff placed at the end. The artery was turned inside out over the cuff and ligated. The vein segment was grafted between the 2 ends of the carotid artery.
Tissue Preparation
Vein grafts were harvested at 1 day and 1, 4, and 8 weeks
postoperatively (4 to 8 mice at each time point per group) by cutting
the implanted segments from the native vessels at the cuff end.
Histology and Lesion Quantification
Histological sectioning began at the center of
the graft to avoid the effects of the cuff. The thickness of the vessel
wall was determined by measuring 4 regions of a section along a cross
and was recorded in micrometers (mean±SD) as described
elsewhere.14 For neointimal area measurement,
sections were reviewed with a BX60 microscope equipped with a Sony 3CCD
camera and television monitor. The neointimal area was
determined by subtracting the area of the lumen from the area enclosed
by the border of the adventitia.
Immunofluorescent Staining
The procedure used for immunofluorescent staining was
similar to that described previously.16 Briefly, serial
5-µm-thick frozen sections were labeled with a rat monoclonal
antibody against mouse MAC-1 (CD11b/CD18) leukocytes, a rabbit
polyclonal antibody against mouse ICAM-1 (Santa Cruz Biotechnology), or
a mouse monoclonal antibody against -actin conjugated with FITC.
En Face Immunofluorescence
The procedure used in this experiment was similar to that
described previously.17 In brief, each vein graft segment
was cut longitudinally, mounted endothelium side up
onto a glass slide (2.6x7.5 cm), and air dried for 1 to 2 hours at
room temperature. The segments were incubated with appropriately
diluted rat monoclonal antibody to MAC-1 and visualized with
FITC-labeled rabbit anti-rat Ig. MAC-1–positive cells were counted at
10x40 magnification with water immersion objectives in 10
fields of each segment.
SMC Culture and Treatment and Leukocyte/SMC Adhesion Assay
Vascular SMCs from ICAM-1 -/- and +/+ mice were cultivated
from their aortas as described previously.18 Briefly,
mouse thoracic aortas were removed, and the intima and media were
carefully dissected from the vessel under an anatomic microscope, cut
into pieces (1x1x0.1 mm), and implanted onto a gelatin
(0.02%)-coated plastic bottle. SMCs were passaged 7 to 10 days after
implantation. They were treated with 100 ng/mL tumor necrosis
factor- (TNF-) and assessed for immunofluorescent
staining or cell adhesion assays. The procedure for splenocyte
isolation and leukocyte adhesion assays was similar to that described
elsewhere.17
Statistical Analysis
Statistical analyses were performed on a Macintosh
computer with the Mann-Whitney U test and ANOVA,
respectively.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Reduced Neointima Hyperplasia in ICAM-1 -/- Mice
The venous wall of ICAM-1 -/- and wild-type mice is composed of intima, a monolayer of endothelium, media, 1 or 2 layers of SMCs, and adventitia, a small amount of connective tissues (Figures 1A
and 1B). Vein grafts of
wild-type mice at 4 and 8 weeks (Figures 1C and 1E) showed
neointimal hyperplasia (ie, thickening of the vessel wall
up to 10 or 20 layers of cells). Interestingly, neointimal
lesions of vein grafts in ICAM-1 -/- mice showed a marked reduction
at 4 as well as at 8 weeks (Figures 1D and 1F).
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Figure 2 summarizes data for
neointima thickness and area measured microscopically.
Thickening of the vein grafts began as early as 2 weeks after surgery
(data not shown). A significant difference was found between groups of
ICAM-1 -/- and wild-type mice (P<0.001).
Neointimal hyperplasia of vein grafts in ICAM-1 -/- was
reduced 30% to 50% compared with that of wild-type control animals
(Figure 2).
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ICAM-1 Expression in Vein Grafts
ICAM-1 is thought to be involved in the firm adhesion step in
leukocyte infiltration and has been shown to be highly expressed in
atherosclerotic lesions in humans and
hypercholesterolemic animals.19 20 21 22 It
would be interesting to assess whether ICAM-1 is also expressed in the
grafted veins. Serial cross sections of vein specimens from both ICAM-1
-/- and wild-type mice were immunologically stained with rabbit
anti–ICAM-1 antibodies. There was scant immunostaining
for ICAM-1 on the endothelium of freshly excised veins
but significantly increased staining on the surface of vein grafts 1
day after surgery (Figure 3A).
ICAM-1–positive staining was also observed in sections of vein grafts
of wild-type mice at 1 and 4 weeks (Figures 3B and 3C). The
pattern of ICAM-1 staining in the vein grafts shown in Figure 3
was different. In the 1-day graft, most surface areas in the intima had
become more intensively stained (Figure 3A), whereas vein grafts
at 1 and 4 weeks displayed elevated ICAM-1 content in the
endothelial and subendothelial regions
(ie, not only in the intima, but also in the media and adventitia;
Figures 3B and 3C). As expected, there was no positive staining
for ICAM-1 in the vein grafts of ICAM-1 -/- mice (Figure 3D).
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Decreased Leukocyte Adhesion to and Infiltration in Vein Grafts of
ICAM-1 -/- Mice
We previously adopted the vessel en face
immunofluorescence method17 for
semiquantification of cells that adhere to the
endothelium of vascular segments. This method was
generally useful in the clarification of the kinetics and
phenotypes of cells that adhere to vascular
endothelial surface in vivo. Nonspecific reactivity was
minimal in the negative control labeled with normal rat serum (Figure 4A), and cells that adhered to the
endothelial surface were positively stained with a rat
monoclonal antibody recognizing MAC-1+ leukocytes
(CD11b/CD18; Figures 4B through 4D). A large number of
MAC-1+ leukocytes were observed adherent to the
endothelium of vein graft segments of wild-type mice 1
day after surgery (Figure 4C), whereas cells adherent to the
surface of vein grafts from ICAM-1 -/- mice were much less profound
(Figure 4D). Occasionally, MAC-1+–stained
cells were also seen on the surface of freshly harvested vein segments
(Figure 4B). Figure 4E shows statistical data from 5
animals of each group and indicates a significant difference in
adherent cells between ICAM-1 -/- and ICAM-1 +/+ vein grafts. These
results indicate that leukocyte adhesion to the
endothelium is one of the earliest cellular events in
vein graft disease.
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There is evidence of increased expression of monocyte chemotactic
protein-1 in vein grafts associated with the development of vein graft
intimal hyperplasia.23 Cells that tether to the
endothelium can be followed with transmigration and
localization in the vein graft. Using immunofluorescent
techniques, we found MAC-1–positive cells in vein grafts at 4 and 8
weeks. MAC-1+ cells are
monocytes/macrophages, natural killer cells, and granulocytes.
The majority of infiltrating cells in neointima were
mononuclear cells (ie, monocytes/macrophages). Abundant
infiltration of these positive cells was found in the intima, media,
and adventitia of 4-week vein grafts (Figure 5A; 50 to 200 positive cells/x400
field), whereas small numbers of MAC-1+ cells
were seen in the vein grafts of ICAM-1 -/- mice (Figure 5B; 20
to 96 positive cells/x400 field). MAC-1+
monocytes/macrophages were also detected at the luminal surface
at 8 weeks after engraftment in both ICAM-1 -/- and +/+ mice (Figures 5C and 5D), but these positive cells were rarely seen in the
neointima of 8-week grafts in ICAM-1 -/- mice (Figure 5D).
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Figure 6 shows
histological data for 4- and 8-week vein grafts from
both ICAM-1 -/- and wild-type mice. Mononuclear cell infiltration in
vein segments of wild-type mice was more predominant than those of
ICAM-1 -/- mice. When cell nuclei in the intima and media of
neointima of grafted vessels were counted in 100-µm
lengths, total cell numbers were significantly higher in 4- and 8-week
grafts of wild-type mice (Figure 6E). These observations
indicate that ICAM-1 is important in the mediation of leukocyte
adhesion and transmigration in vein grafts.
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SMCs Expressed ICAM-1 and Leukocyte Adhesion
We previously demonstrated the presence of abundant SMCs in venous
bypass graft lesions 4 and 8 weeks after surgery.14 Figure 3
shows ICAM-1–positive staining not only localized on the
surface but also inside the neointima. To test whether SMCs
express ICAM-1 in vein grafts, a double immunofluorescent
labeling was performed. Strong staining for ICAM-1 was observed
in sections from vein segments of wild-type mice 4 weeks
postoperatively (Figure 7a) but not of
ICAM-1–deficient mice (Figure 7b). Importantly, a large portion
of positive-stained cells were -actin–positive SMCs (Figure 7a).
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To study ICAM-1 expression and the role of this molecule in cell
adhesion, aortic SMCs from both ICAM-1 -/- and +/+ mice were
cultivated and treated with TNF-, and ICAM-1 was examined with
immunofluorescence with the specific antibody
against ICAM-1. TNF-–stimulated ICAM-1 induction was observed in
ICAM-1 +/+, but not ICAM-1 -/-, SMCs (Figures 8A to 8C). Untreated ICAM-1 +/+ SMCs had
very weak staining (Figure 8B). Furthermore, we investigated
SMC/leukocyte adhesion in vitro, where ICAM-1 -/- and +/+ SMCs were
treated with TNF- and incubated with spleen leukocytes prepared from
ICAM-1 +/+ mice. Leukocyte adhesion to the ICAM-1 +/+ SMC surface
increased 2- to 3-fold after treatment with TNF- and was
significantly lower in ICAM-1 -/- SMCs. Partial block of adhesion
could be achieved through preincubation of spleen leukocytes with the
monoclonal antibody directed to MAC-1, and this block was less
effective on ICAM-1 -/- SMCs. These findings suggest that ICAM-1
expressed in SMCs is responsible, at least in part, for leukocyte
adhesions.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, we established and characterized a new model for the study of neointima formation of venous bypass grafts in mice.14 In the present study, we demonstrated that this mouse model is useful for investigation of the role of adhesion molecules in vein graft disease with knockout mice. When vein isografts were performed in ICAM-1 -/- mice, intimal lesions were reduced up to 50% compared with wild-type control animals. The mechanism of reduced neointimal hyperplasia is due to the lack of ICAM-1 expression, resulting in reduction of leukocyte adhesion to the endothelium of vein grafts at the early stage and a lower rate of accumulation of monocytes/macrophages in neointimal lesions at the late stage.
In the present study, we demonstrate that a hallmark of vein grafts
in wild-type mice is ICAM-1 expression between 1 day to 8 weeks
postoperatively. What is the initial factor that results in adhesion
molecule expression on the endothelial cells of grafted
veins? Surgical or traumatic and ischemic injury to the vein
segments may be in part responsible for ICAM-1 induction in the vein
grafts, but we posit that mechanical stress plays a role in ICAM-1 gene
expression via signal transduction pathways leading to NF-
B
activation. In grafted veins, mechanical force on the vessel segment
suddenly increases >10-fold (arterial versus venous blood
pressure), which provides a strong stimulus to vascular
endothelial and SMCs. We previously demonstrated that
acutely elevated blood pressure and mechanical stress activate
growth factor receptor/mitogen-activated protein kinase signal
pathways,24 25 26 27 which are closely related to NF-B
activation. Other reports have established that the exposure of
endothelial cells to shear (mechanical) stress results
in increased expression of ICAM-1 and monocyte chemotactic protein-1
via the activation of transcription factor NF-B and
activator protein-1.28 29 30 31 32 33 34 These molecules are
essential for leukocyte/endothelial cell interaction
and, subsequently, cell infiltration, which is characteristic of the
early lesions of vein grafts that undergo elevated blood pressure.
Thus, our observations, together with others, suggest that mechanical
stress is one of the most important factors in the initiation of ICAM-1
expression in vein grafts.
Although the importance of ICAM-1 in the mediation of cell adhesion to
the endothelium has been established, little is known
about the role of ICAM-1 expressed in vascular SMCs.35 36
Given the facts that SMCs express ICAM-1 associated with
monocyte/macrophage accumulation in vein grafts and that SMCs
of ICAM-1 -/- mice do not express ICAM-1 correlated with reduced
neointimal lesions, we postulate the role of ICAM-1
expression on SMCs in the development of intimal hyperplasia via 3
ways. First, the interaction of MAC-1 and ICAM-1 expressed on SMCs may
initiate intracellular signaling necessary for cytokine
secretion by monocytes/macrophages. Support for this notion
comes from the fact that macrophage inflammatory protein-1
production was induced in monocytes cultured on ICAM-1–coated
plates.37 Second, the binding of MAC-1 to ICAM-1 expressed
on SMCs may be responsible for monocyte retardation in the vessel wall.
Third, it has been reported that expression of ICAM-1 on SMCs may be
relevant to the phenotypical change of SMCs,38 which is
considered to be essential to the migration and proliferation of SMCs
in the pathogenesis of atherosclerosis.39
Therefore, the binding of MAC-1 to ICAM-1 on SMCs might result in
intracellular signaling within SMCs, which initiates the gene
expression needed for phenotypical change.
In summary, nearly all veins implanted into the arterial circulation in patients develop intimal hyperplasia within 4 to 6 weeks, which represents the foundation for later development of venous bypass graft atheroma.2 We demonstrated that ICAM-1 is critical in the accumulation of monocytes/macrophages responsible for neointimal hyperplasia in early grafted vessels. If ICAM-1 expression of vein grafts in patients is inhibited by locally applied drugs, such as aspirin, or neutralized by anti–ICAM-1 antibodies, reduced intimal lesions may be seen.
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Acknowledgments |
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This work was supported by grants P-13099-BIO (to Dr Xu) from the Austrian Science Fund and P7919 (to Dr Xu) from the Jubiläumsfonds of the Austrian National Bank.
Received September 16, 1999; accepted November 29, 1999.
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 L. Zhang, P. Sivashanmugam, J.-H. Wu, L. Brian, S. T. Exum, N. J. Freedman, and K. Peppel Tumor Necrosis Factor Receptor-2 Signaling Attenuates Vein Graft Neointima Formation by Promoting Endothelial Recovery Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 284 - 289. [Abstract] [Full Text] [PDF]
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 T. Schachner, G. Laufer, and J. Bonatti In vivo (animal) models of vein graft disease. Eur. J. Cardiothorac. Surg., September 1, 2006; 30(3): 451 - 463. [Abstract] [Full Text] [PDF]
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 T. Schachner Pharmacologic inhibition of vein graft neointimal hyperplasia J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 1065 - 1072. [Abstract] [Full Text] [PDF]
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U. Mayr, Y. Zou, Z. Zhang, H. Dietrich, Y. Hu, and Q. Xu Accelerated Arteriosclerosis of Vein Grafts in Inducible NO Synthase-/- Mice Is Related to Decreased Endothelial Progenitor Cell Repair Circ. Res., February 17, 2006; 98(3): 412 - 420. [Abstract] [Full Text] [PDF]
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T. Walker, H. P. Wendel, L. Tetzloff, O. Heidenreich, and G. Ziemer Suppression of ICAM-1 in human venous endothelial cells by small interfering RNAs Eur. J. Cardiothorac. Surg., December 1, 2005; 28(6): 816 - 820. [Abstract] [Full Text] [PDF]
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Z. A. Ali, C. A. Bursill, Y. Hu, R. P. Choudhury, Q. Xu, D. R. Greaves, and K. M. Channon Gene Transfer of a Broad Spectrum CC-Chemokine Inhibitor Reduces Vein Graft Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, August 30, 2005; 112(9_suppl): I-235 - I-241. [Abstract] [Full Text] [PDF]
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T. Sakaguchi, T. Asai, D. Belov, M. Okada, D. J. Pinsky, A. M. Schmidt, and Y. Naka Influence of ischemic injury on vein graft remodeling: Role of cyclic adenosine monophosphate second messenger pathway in enhanced vein graft preservation J. Thorac. Cardiovasc. Surg., January 1, 2005; 129(1): 129 - 137. [Abstract] [Full Text] [PDF]
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L. Zhang, K. Peppel, L. Brian, L. Chien, and N. J. Freedman Vein Graft Neointimal Hyperplasia Is Exacerbated by Tumor Necrosis Factor Receptor-1 Signaling in Graft-Intrinsic Cells Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2277 - 2283. [Abstract] [Full Text] [PDF]
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 Q. Xu Mouse Models of Arteriosclerosis: From Arterial Injuries to Vascular Grafts Am. J. Pathol., July 1, 2004; 165(1): 1 - 10. [Abstract] [Full Text] [PDF]
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E. Torsney, U. Mayr, Y. Zou, W. D. Thompson, Y. Hu, and Q. Xu Thrombosis and Neointima Formation in Vein Grafts Are Inhibited by Locally Applied Aspirin Through Endothelial Protection Circ. Res., June 11, 2004; 94(11): 1466 - 1473. [Abstract] [Full Text] [PDF]
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S. Kwei, G. Stavrakis, M. Takahas, G. Taylor, M. J. Folkman, M. A. Gimbrone Jr, and G. Garcia-Cardena Early Adaptive Responses of the Vascular Wall during Venous Arterialization in Mice Am. J. Pathol., January 1, 2004; 164(1): 81 - 89. [Abstract] [Full Text] [PDF]
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Y. Hu, F. Davison, Z. Zhang, and Q. Xu Endothelial Replacement and Angiogenesis in Arteriosclerotic Lesions of Allografts Are Contributed by Circulating Progenitor Cells Circulation, December 23, 2003; 108(25): 3122 - 3127. [Abstract] [Full Text] [PDF]
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Q. Xu, Z. Zhang, F. Davison, and Y. Hu Circulating Progenitor Cells Regenerate Endothelium of Vein Graft Atherosclerosis, Which Is Diminished in ApoE-Deficient Mice Circ. Res., October 17, 2003; 93 (8): e76 - e86. [Abstract] [Full Text] [PDF]
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A. Agarwal and M. S. Segal Intimal Exuberance: Veins in Jeopardy Am. J. Pathol., June 1, 2003; 162(6): 1759 - 1761. [Full Text] [PDF]
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J.H.P. Lardenoye, M.R. de Vries, C.W.G.M. Lowik, Q. Xu, C.R. Dhore, J.P.M. Cleutjens, V.W.M. van Hinsbergh, J.H. van Bockel, and P.H.A. Quax Accelerated Atherosclerosis and Calcification in Vein Grafts: A Study in APOE*3 Leiden Transgenic Mice Circ. Res., October 4, 2002; 91(7): 577 - 584. [Abstract] [Full Text] [PDF]
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Y. Hu, M. Mayr, B. Metzler, M. Erdel, F. Davison, and Q. Xu Both Donor and Recipient Origins of Smooth Muscle Cells in Vein Graft Atherosclerotic Lesions Circ. Res., October 4, 2002; 91 (7): e13 - e20. [Abstract] [Full Text] [PDF]
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U. Mayr, M. Mayr, C. Li, F. Wernig, H. Dietrich, Y. Hu, and Q. Xu Loss of p53 Accelerates Neointimal Lesions of Vein Bypass Grafts in Mice Circ. Res., February 8, 2002; 90(2): 197 - 204. [Abstract] [Full Text] [PDF]
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Y. Hu, A. H. Baker, Y. Zou, A. C. Newby, and Q. Xu Local Gene Transfer of Tissue Inhibitor of Metalloproteinase-2 Influences Vein Graft Remodeling in a Mouse Model Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1275 - 1280. [Abstract] [Full Text] [PDF]
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H. Dietrich, Y. Hu, Y. Zou, U. Huemer, B. Metzler, C. Li, M. Mayr, and Q. Xu Rapid Development of Vein Graft Atheroma in ApoE-Deficient Mice Am. J. Pathol., August 1, 2000; 157(2): 659 - 669. [Abstract] [Full Text] [PDF]
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U. Mayr, M. Mayr, C. Li, F. Wernig, H. Dietrich, Y. Hu, and Q. Xu Loss of p53 Accelerates Neointimal Lesions of Vein Bypass Grafts in Mice Circ. Res., February 8, 2002; 90(2): 197 - 204. [Abstract] [Full Text] [PDF]
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